Huntington's disease (HD) and other expanded polyglutamine diseases are late- onset neurodegenerative diseases caused by expansion of a glutamine repeat in the mutant protein. Currently, no cure or effective treatment for these agonizing and lethal diseases exists. The pathogenic target of the expanded glutamine repeat is unknown. We find that the polyglutamine domain of Huntingtin (Htt) binds to and inhibits the activity of several acetyltransferases (e.g.CBP, p300, and P/CAF) and reduces the level of acetylated histones in cell culture. We have developed and used two Drosophila models of HD to test the possibility that neuropathology may result from reduced levels of acetylation and transcription. We find that inhibition of the deacetylation process by two independent mechanisms Le. genetically or pharmacologically (HDAC inhibitors) reduces lethality and arrests photoreceptor neuron degeneration. These results strongly implicate the state of acetylation in the pathogenic process. As several HDAC inhibitors, including SAHA, are currently FDA approved for use in other clinical settings or are in Phase I clinical trials, HDAC inhibitors can now be seriously considered as potential therapeutic agents for HD and related diseases. This represents one of the early cases where potentially useful pharmacologic agents have been identified in a Drosophila model of disease. Here we propose to extend these studies using the Drosophila model. In both flies and man there are families of HAT (Histone Acetyl Transferase) and HDAC (Histone DeACetylase) genes (-11 HATs and ~9 HDAC related genes). In this project, we will determine whether all or just some of these genes are relevant to polyglutamine pathogenesis and we will determine whether contributions are additive. These data will improve our understanding of the genetic and molecular basis of pathogenesis, they will identify new targets for therapeutics and they will reveal whether combination therapies targeted at multiple enzymes in the HAT/HDAC cycle might be effective. PERFORMANCSEITE(S)(organizatiocnit,ys, tate) University of California, Irvine, Irvine, CA 92697 KEY PERSONNEL See instruc_ons. Use conl/nua_/onpages as neededto providethe requiredinformationinthe format shown below. Startwith PrincipalInvestigator. List all other key personnel in alphabetical order, last name first. Name Organization Roleon Project J. Lawrence Marsh, Ph.D. Devel.& Cell Biology, UC Irvine PI Leslie M. Thompson Ph.D. Psychiatry and Hum Behavior, UC Irvine Co-PI Namita Agrawal Ph.D. Devel.& Cell Biology, UC Irvine Post graduate researcher Tamas Lukacsovich Ph.D. Devel.& Cell Biology, UC Irvine Professional researcher 50% Martin Hicks Devel.& Cell Biology, UC Irvine graduate student Lazlo Bodai Devel.& Cell Biology, UC Irvine Junior specialist 67% Judit Pallos Devel.& Cell Biology, UC Irvine Junior specialist 67% Disclosure Perm/ss/on Statement. Applicable tO$BIPJSTTR Only. See instructions. [] Yes [] No , PHS 398 (Rev. 05/01) Page_2 Form Page 2 + Use_-inch MARGINS. Number pages consecutivelyat the bottomthroughoutthe application.Do not use suffixessuchas 3a, 3b. PdndpInavl estigator/PDroigreract(mLoarst, first,middle): Marsh. J. Lawrence The name of the principalinvestigator/programdirectormust be providedat the top of each printedpage and each continuationpage. Type density and size must conform to limits and specifications provided in the PHS 398 Instructions. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ..................................................................................................................................... 1 Description,